Oral osmotic device with hydrogel driving member

ABSTRACT

An osmotic device (10) for delivering a beneficial drug, such as an anti-fungal, into the mouth of a human patient is disclosed. The device (10) has a size and shape adapting it to be comfortably retained in the mouth for extended periods of time. The device (10) comprises a wall (12) surrounding a compartment (13) housing a layer of an agent (14) that is insoluble to very soluble in aqueous biological fluids, e.g., saliva, and a layer (16) of a fluid swellable, hydrophilic polymer. A passageway (17) in the wall (12) connects the agent (14) with the exterior of the device (10). The wall (12) is permeable to the passage of aqueous biological fluid but substantially impermeable to the passage of the hydrophilic polymer (16). In one embodiment the beneficial agent (14) has a different color than the hydrophilic polymer (16). The wall (12) is sufficiently translucent to permit the patient to see the amount of drug/beneficial agent (14) remaining to be delivered. Marking lines (19) may be provided on the wall (12) indicating the amount of drug/agent (14) which has been delivered and/or the amount remaining to be delivered.

This application is a continuation of U.S. Ser. No. 08/171,875 filedDec. 22, 1993, now U.S. Pat. No. 5,776,493 issued on Jul. 7, 1998 whichapplication is a continuation of U.S. Ser. No. 07/781,234 filed Jan. 7,1992, now abandoned, which Ser. No. 07/781,234 is a continuation-in-partof PCTUS9003882 filed on Jul. 11, 1990, which PCTUS9003882 is acontinuation-in-part of U.S. Ser. No. 380,229 filed Jul. 14, 1989 nowU.S. Pat. No. 5,021,053 issued Jun. 4, 1991.

1. TECHNICAL FIELD

This invention pertains to an osmotic device for delivering a beneficialagent into the oral cavity of a patient. More particularly, theinvention relates to an osmotic device comprising a shaped semipermeablewall surrounding a compartment containing a beneficial agent that isinsoluble to very soluble in an aqueous fluid, and a layer of awater-swellable hydrophilic polymer driving member. A passageway throughthe wall connects the exterior of the device with an agent fordelivering the agent from the device into the oral cavity. Means areprovided for displaying the amount of agent remaining to be delivered.

2. BACKGROUND ART

Osmotic devices for delivering beneficial agents to environments of useare known to the prior art in U.S. Pat. Nos. 3,845,770 and 3,916,899issued to Theeuwes et al. The osmotic devices disclosed in those patentscomprise a semipermeable wall that surrounds a compartment containing anagent. The wall is permeable to the passage of an external fluid, andsubstantially impermeable to the passage of agent. There is a passagewaythrough the wall for delivering the agent from the device. These devicesrelease agent by fluid being imbibed through the wall into thecompartment at a rate determined by the permeability of the wall and theosmotic pressure gradient across the wall to produce an aqueous solutioncontaining agent that is dispensed through the passageway from thedevice. These devices are extraordinarily effective for delivering anagent that is soluble in the fluid and exhibits an osmotic pressuregradient across the wall against the fluid, and for delivering an agentthat has limited solubility in the fluid and is admixed with anosmotically effective compound that is soluble in the fluid and exhibitsan osmotic pressure gradient across the wall against the fluid. Devicesof this type are typically designed to be swallowed or implanted todeliver a drug or other beneficial agent to the body.

In U.S. Pat. No. 4,111,202, the delivery kinetics of the device areenhanced by manufacturing the device with an agent compartment and anosmagent compartment separated by a film, which film is movable from arested to an expanded state. The device delivers agent by fluid beingimbibed through the wall into the osmagent compartment producing asolution that causes the compartment to increase in volume and act as adriving force that is applied against the film. This force urges thefilm to expand against the agent compartment and correspondinglydiminish the volume of this compartment, whereby agent is dispensedthrough the passageway from the device. While this device operatessuccessfully for its intended use, and while it can deliver numerousdifficult to deliver agents, its use is somewhat limited because of themanufacturing steps needed for fabricating and placing the movable filmin the device.

In U.S. Pat. No. 4,327,725 Cortese et al provided an osmotic dispensingdevice for delivering a beneficial agent which, because of itssolubility in an aqueous biological fluid is difficult to deliver inmeaningful amounts at controlled rates over time. The osmotic device ofthis patent comprises a semipermeable wall surrounding a compartmentcontaining a beneficial agent that is insoluble to very soluble in anaqueous biological fluid and an expandable hydrogel. In operation, thehydrogel expands in the presence of external fluid that is imbibed intothe device and in some operations mixes with the beneficial agents,thereby forming a dispensable formulation that is dispensed through thepassageway from the device. This device operates successfully for itsintended use, and it delivers many difficult to deliver beneficialagents for their intended purpose.

When administering a drug buccally (i.e., by absorption of the drugthrough the highly vascularized buccal tissues of the mouth) a number ofconditions are present which makes it difficult to effectively deliverdrug in a therapeutically effective amount for a prolonged period oftime (e.g., for periods greater than several minutes). For example, whena patient is given a drug-containing lozenge, there is a naturaltendency to suck and chew on the lozenge thereby effectively reducingthe time period during which the drug can be buccally administered bythe lozenge. In addition, the action of saliva and swallowing by thepatient effectively reduces the concentration of drug along the buccalmembranes of the oral cavity and further causes much of the drug to beswallowed, in many cases rendering it inactive upon encountering the lowpH environment of the stomach. This has been a particular problem intreating diseases of the mouth which require constant localadministration of drug. One such disease condition is candidiasis of theoral cavity. A recent study has shown that 94% of male patients havingacquired immunodeficiency syndrome (AIDS) and 72% of those withAIDS-related complex (ARC) had oral candidiasis (Barr & Marder, AIDS: AGuide For Dental Practice, pp. 53-62, 1987). Recommended treatment oforal candidiasis is by continuous dosing of selected anti-fungal agentsin the mouth, pharynx and oesophagus. Typically, therapeuticallyrecommended doses of nystatin, amphotericin B or miconazole, either inthe form of liquid rinses or slowly dissolving pastilles and tabletshave been used to treat oral candidiasis. Unfortunately, when theanti-fungal agents are administered by gargling or with rinses, theanti-fungal agents are cleared from the mouth in a matter of minutes.While the duration of drug delivery is increased somewhat using slowlydissolving pastilles and tablets, typically these release drug for nomore than about 15 to 20 minutes. Accordingly, these dosage formsrequire frequent repetitive dosing (e.g., gargling every five minutes ortaking a lozenge 3-4 times per hour) in order to effectively treat thecondition.

Thus, there has been a clear need in the art of treating oral diseases,such as oral candidiasis, for a dosage form which is able tocontinuously deliver therapeutically effective amounts of drug or otherbeneficial agent into the oral cavity for extended periods of time, i.e.periods greater than about 15 to 20 minutes.

In response to the problem of short duration of drug delivery fromrinses, pastilles and tablets, the use of an elementary osmotic pump todeliver medication to the buccal tissues has been suggested. Elementaryosmotic pumps are typically formed by compressing a tablet of anosmotically active drug (or an osmotically inactive drug in combinationwith an osmotically active agent or osmagent) and then coating thetablet with a semipermable membrane which is permeable to an exterioraqueous-based fluid but impermeable to the passage of drug and/orosmagent. One or more delivery orifices may be drilled through thesemipermeable membrane wall. Alternatively, orifice(s) through the wallmay be formed in situ by incorporating leachable pore forming materialsin the wall. In operation, the exterior aqueous based fluid is imbibedthrough the semipermeable membrane wall and contacts the drug and/orsalt to form a solution or suspension of the drug. The drug solution orsuspension is then pumped out through the orifice as fresh fluid isimbibed through the semipermeable membrane.

While the use of elementary osmotic pumps has proven to be verysuccessful in delivering drugs through the gastro-intestinal (GI) tract(i.e., by swallowing the elementary osmotic pump), there are severalproblems with buccal administration. As with drug-containing lozenges,there is a natural tendency for the patient to suck and chew on thedrug-containing elementary osmotic pumps. Chewing in particular tends tocompress the deformable membrane wall, thereby squeezing the drugsolution or suspension out of the device at an accelerated rate. Theduration of drug delivery is therefore severely curtailed. For example,when an elementary osmotic pump, designed to deliver drug at arelatively constant rate over a period of 12 to 24 hours within the GItract, is placed in the oral cavity and subjected to patient sucking andchewing, the device delivers the entire drug dose relatively quickly,sometimes in less than about an hour.

Thus, there has been a need in the art of treating oral diseases for adosage form which is osmotically driven but which is able tocontinuously deliver a drug within the mouth to the buccal membranes andwhich is relatively unaffected by the patient sucking and chewing on thedevice.

Another proposed solution to the problem of short duration of drugdelivery from rinses, pastilles, and tablets, has been a delivery devicecomprised of a hydrophilic polymer having a drug dispersed therein. Whenplaced between the cheek and gum of a patient, the hydrophilic polymerabsorbs moisture from the buccal membrane, eventually adhering itself tothe membrane surface. While it is desirable from the standpoint ofpatient comfort and convenience to adhere the delivery platform directlyto the buccal membrane, this can create a problem when delivering a drughaving a tendency to cause irritation. When delivering an irritatingdrug, these devices tend to magnify the irritation since the device isadhered to the buccal membrane and maintains a high concentration of theirritating drug at a single membrane site.

Thus, there has been a need in the art of treating oral diseases for adosage form which is able to continuously deliver a potentiallyirritating drug for extended periods of time without causing irritation.

Of course, with any dosage form designed to deliver a drug into the oralcavity for an extended period of time, means must be provided foralerting the patient when a predetermined dose of the drug has beendelivered. For example, in cases where the recommended treatment iscontinuous delivery of drug into the mouth of the patient, a signalingmeans for alerting the patient when the entire dosage has been deliveredis required. In the case of a dosage form designed to deliver apredetermined percentage of the dose buccally and the remainder of thedose through the GI tract, the dosage form must be provided with meansfor signaling the patient when the predetermined perecentage of the dosehas been delivered.

DISCLOSURE OF THE INVENTION

Accordingly, it is an object of this invention to provide an osmoticdevice for the controlled delivery of a beneficial agent to the oralcavity of an animal, and in particular a human, for an extended periodof time.

It is another object of the invention to provide an oral osmotic deviceuseful for delivering an agent into the mouth of a patient, which agentis difficult to deliver and can be delivered by the subject device at apharmaceutically effective rate and over an extended period of time.

It is another object of the invention to provide an oral osmotic devicehaving a compartment containing an active agent that can be frominsoluble to very soluble in an aqueous fluid which is present in theoral cavity, and an expandable driving member consisting of a layer of ahydrophilic polymer, which operates to diminish the volume occupied bythe active agent, thereby delivering the agent from the device at acontrolled rate over an extended period of time, the agent beingreleased from the device in the form of a solution and/or suspension.

It is yet another object of the invention to provide an oral osmotictherapeutic device that can administer a complete pharmaceutical dosageof a very soluble or a poorly soluble agent, at a controlled andcontinuous rate into the mouth of an animal, for an extended deliveryperiod and which device signals the animal when the complete dose ofbeneficial agent has been delivered.

It is a further object of the invention to provide an oral osmotictherapeutic device that can administer a complete pharmaceutical dosageof a very soluble, or a poorly soluble agent, at a controlled andcontinuous rate into the mouth of a human, for an extended deliveryperiod and which device displays the amount of beneficial agent whichhas been delivered and the amount of beneficial agent which stillremains in the device to be delivered.

It is a still further object of the invention to provide an oral osmotictherapeutic device that can administer a potentially irritating druginto the mouth of a human for an extended period of time without causingirritation to the buccal membrane.

Other objects, features, aspects and advantages of the invention will bemore apparent to those versed in the art from the following detailedspecification taken in conjunction with the figures and the accompanyingclaims.

This invention concerns an osmotic device for controlled delivery of anactive beneficial agent into the oral cavity of an animal, such as ahuman. The device comprises a wall formed of a material which ispermeable to the passage of an external aqueous fluid which is presentin the oral cavity (e.g., saliva). The wall material may be eithersubstantially impermeable or partially permeable to the passage of theactive agent. The wall surrounds and forms a compartment thatcommunicates with the exterior of the device through one or morepassageways in the wall. The compartment contains an active agentexhibiting any degree of solubility in the aqueous fluid. For example,the agent may be soluble in the exterior fluid and exhibit an osmoticpressure gradient across the wall against the fluid, or the agent may becompletely insoluble in the fluid and be admixed with an osmotic agentwhich exhibits an osmotic pressure gradient across the wall against thefluid. In either instance, the agent is next to the passageway. Thecompartment also contains a layer of an expandable driving member formedof a water-swellable hydrophilic polymer. The wall material issubstantially impermeable to the hydrophilic polymer. The hydrophilicpolymer absorbs fluidimbibed into the compartment, and can expand from arested to an expanded state. The hydrophilic polymer is in contact withthe agent formulation and positioned distant from the passageway. Agentis released form the device by the combined actions of fluid beingimbibed through the wall into the compartment producing a solution orsuspension containing agent, and by fluid being imbibed by thehydrophilic polymer causing it to expand and increase in volume, therebyexerting a force against the solution or suspension that decreases theirrespective volume, whereby the agent is released through the passagewayat a rate controlled by the permeability of the wall, the osmoticpressure gradient across the wall, and the rate of expansion of thedriving hydrophilic polymer over a prolonged delivery period. The devicehas a size and shape allowing it to be comfortably retained in the oralcavity for an extended period of time.

The device is provided with a mechanism for signaling the animal whenthe dose of beneficial agent has been delivered from the device. In oneembodiment, the mechanism includes providing the layer of the beneficialagent with a taste which contrasts with the hydrophilic polymer layertaste. In a preferred embodiment, the layer of active agent contains afirst flavoring agent while the hydrophilic polymer layer contains asecond flavoring agent having a flavor easily distinguishable from theflavor of the first flavoring agent. During use, the active agent isco-delivered with the first flavoring agent. The patient can easilyrecognize that the device is delivering drug due to the flavor of thefirst flavoring agent. Eventually, the entire dose of active agent isdelivered. At this point, the device also stops delivering the firstflavoring agent. Thereafter, the device begins delivering thehydrophilic polymer and the second flavoring agent. Upon tasting thesecond flavoring agent, the patient knows that the device has deliveredthe entire dose of beneficial agent.

In another embodiment, the mechanism for signaling the animal alsodisplays the amount of beneficial agent present in the device. In apreferred embodiment, the active agent and the hydrophilic polymer havecontrasting colors. The semipermeable wall is made sufficientlytranslucent to permit the patient to see the relative amounts of activeagent and hydrophilic polymer present in the compartment.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a top view of a preferred embodiment of an osmotic device foradministering a beneficial agent into the oral cavity of an animal;

FIG. 2 is a side view of the oral osmotic device shown in FIG. 1;

FIG. 3 is a side sectional view of the osmotic device of FIGS. 1 and 2illustrating the internal structure of the device;

FIG. 4 is a side sectional view of the osmotic device of FIG. 3 afterdelivering a portion of the beneficial agent from the device;

FIG. 5 is a graph depicting the cumulative amount of beneficial agentreleased from (i) a device according to the present invention and (ii)two prior art delivery devices.

In the drawings (which are not drawn to scale) and the specification,like parts in related figures are identified by like numerals.

DETAILED DESCRIPTION OF THE INVENTION

Turning now to the drawings, one example of an oral osmotic device isshown in FIGS. 1 through 4, and is indicated by the numeral 10. Device10 is comprised of a wall 12 that surrounds and forms a compartment 13,as seen in the sectional views of FIGS. 3 and 4. Compartment 13comprises a layer of a beneficial agent, identified by dots 14, that canbe from insoluble to very soluble in an exterior aqueous fluid,indicated by dashes 15. When agent 14 is soluble in fluid 15, itexhibits an osmotic pressure gradient across wall 12 against theexterior fluid 15 imbibed into compartment 13. Compartment 13 in anotherembodiment contains a layer of agent 14 that has limited solubility oris substantially insoluble in fluid 15, and it exhibits a limited, or itmay not exhibit any osmotic pressure gradient across wall 12 against theexterior fluid. When agent 14 has a limited solubility, or if it issubstantially insoluble in fluid 15, it can be mixed with an osmagentthat is soluble in the external fluid and exhibits an osmotic pressuregradient across wall 12 against the fluid. Wall 12 is formed of apolymeric material that is substantially permeable to the passage of theexternal fluid, and either impermeable or partially permeable to thepassage of agent and osmagent. The polymer forming wall 12 is non-toxicand it maintains its physical and chemical integrity during the life ofdevice 10.

Compartment 13 further houses a layer of an expandable driving member 16composed of a hydrophilic polymer, optionally cross-linked, whichpossesses osmotic properties such as the ability to imbibe externalfluid and exhibit an osmotic pressure gradient across the wall 12against the fluid. Wall 12 is substantially impermeable to the passageof the hydrophilic polymer in driving layer 16. Layer 16 absorbs fluidimbibed into the compartment and swells. The osmotic pressure of thehydrophilic polymer network is the driving force of the swelling,expanding layer 16. Layer 16 is in contact with agent 14 and at theinterface 18 formed by the hydrophilic polymer and the agent, a thinprecipitate preferably forms. The precipitate is especially preferredwhen the active agent is soluble in the imbibed fluid. The precipitateforms in the presence of a solution containing the agent, or the agentand an osmagent, and it is substantially impervious and restricts thepassage of agent 14 into layer 16. The precipitate further serves as anin situ formed membrane integral with the hydrophilic polymer forapplying pressure against agent 14 during operation of device 10. Whenthe active agent is substantially insoluble, interface 18 can beachieved simply by maintaining a difference in the viscosity values oflayers 14 and 16. For example, layer 16 can be formulated with ahydrophilic polymer having a high molecular weight and a high degree ofcross-linking. In such a case, there is negligible penetration ofinsoluble agent suspension into layer 16.

Device 10 releases agent 14 through one or more passageways 17 in wall12 that communicates agent 14 with the exterior of device 10. Device 10releases agent 14 by fluid being imbibed into compartment 13 in atendency towards osmotic equilibrium at a rate determined by thepermeability of wall 12 and the osmotic pressure gradient across wall12. The imbibed fluid continuously forms a solution of the agent 14, orin cases where the agent 14 has limited or no solubility in the fluid asolution of osmagent containing the agent 14 in suspension, whichsolution in either instance is released by the combined operation ofdevice 10. These operations include the solution/suspension beingosmotically delivered through passageways 17 due to the continuousformation of solution/suspension in the compartment 13, and by thehydrophilic polymer layer 16 swelling and applying pressure against thesolution/suspension thereby delivering it to the exterior of device 10.

Compartment 13 operates to substantially insure that delivery of agent14 from compartment 13 is constant over a prolonged period of time bytwo methods. First, hydrophilic polymer layer 16 operates tocontinuously concentrate agent 14 by imbibing some fluid from agent 14to keep the concentration of agent 14 from falling below saturation.Secondly, layer 16 by imbibing external fluid 15 across wall 12continuously increases its volume, as illustrated by the expansion oflayer 16 from that shown in FIG. 3 to that shown in FIG. 4, therebyexerting a force on agent 14 and diminishing the volume of agent 14,thusly concentrating agent 14 in compartment 13. The swelling of layer16, along with the simultaneous, corresponding reduction of volume ofagent 14, assures the delivery of agent 14 at a controlled rate overtime.

Device 10 of FIGS. 1-4 is designed for oral use, that is, for releasingeither a locally or systemically acting therapeutic agent in the oralcavity of an animal, such as a human, over an extended period of time.Because the device is designed to be retained in the mouth for periodson the order of about 0.5 to 12 hours, the device must have an exteriorshape which is comfortably retained in the mouth. It has been found thatan oblong or elliptically shaped device 10 is preferred from a comfortstandpoint. As shown in FIGS. 1 and 2, device 10 has a length l, a widthw, and a height h. It has been found that devices 10 having an aspectratio, which ratio is the ratio of 1:w, of about 1.2:1 to about 3:1 aremost comfortably retained in the mouths of humans. Preferably, thedevice, 10 has an aspect ratio of about 1.3:1 to about 2:1, and mostpreferably about 1.5:1 to about 1.7:1. In addition, in order to fitcomfortably between the cheek and gum of a patient, the device has aheight of about 0.5 to about 10 mm, preferably about 2 to about 8 mm,and most preferably about 3 to about 5 mm. The device also has a volumeof less than about 2 cm³, preferably about 0.1 to about 0.5 cm³, andmost preferably about 0.25 cm³.

Osmotic delivery device 10 has a mechanism for displaying the amount ofdrug formulation remaining in the device for delivery into the patient.In one preferred embodiment, the display means comprises color contrastbetween the drug formulation 14 and the driving layer 16, in combinationwith a translucent wall 12. In this embodiment, the color of the drugformulation 14 is chosen to provide good visual contrast with the colorof the driving layer 16. The color of the drug formulation 14 can beachieved using any number of coloring techniques known in the art. Forexample, the drug itself may have a natural color which itselfadequately contrasts with the natural color of the driving layer 16. Onthe other hand, a number of pharmaceutically acceptable dyes or coloringagents may be mixed with either the drug formulation 14 and/or thedriving layer 16 in order to provide the appropriate color contrast.Suitable pharmaceutically acceptable coloring agents, both natural andsynthetic, are known in the art. See Remington's PharmaceuticalSciences, 14th Ed., pp 1319-1321.

In accordance with this embodiment of the invention, the patient caneasily determine the amount of agent 14 remaining in compartment 13simply by visually inspecting device 10. For example, the drugformulation 14 may have a white color and the layer 16 may be dyed toachieve a red color. When the device is first placed in the mouth of thepatient, the white and red layers are clearly visible through thetranslucent semipermeable wall 12. After a period of time in thepatient's mouth, the device 10 will imbibe aqueous fluid (e.g., saliva)thereby causing a solution or suspension of the drug 14 to be formed andalso causing the hydrogel 16 layer to expand. Because the drug layer andthe hydrophilic polymer layer have contrasting colors the patient caneasily determine the relative amount of drug remaining in the device fordelivery. This can have a number of useful applications. For example, intreating a condition requiring substantially continuous delivery of drugto the oral cavity, the patient is alerted when the device 10 hasdelivered all of the drug. At this point, only the red hydrophilicpolymer layer remains. This can be checked simply by visually inspectingthe device.

In another embodiment, the device of the present invention can be usedto extend the absorption period of a drug which might be poorly absorbedthroughout certain portions of the GI tract, such as the colon. In sucha case, it may be desirable to administer a predetermined percentage ofa dose of the drug buccally followed by delivery of the remaining doseof drug in the device within the GI tract. One example of such a drug iscaptopril, an anti-hypertensive used for the treatment of heart disease.Another example is the drug cimetidine, a histamine H₂ receptorantagonist used for the treatment of duodenal and gastric ulcers. Insuch cases, the device 10 may be provided with a mark or line 19 on theexternal surface of wall 12 (See FIG. 2). The position of the line 19corresponds to the delivery of the predetermined percentage of the dosefrom the device 10. Thus, when the interface 18 between the hydrophilicpolymer layer 16 and drug 14 layers becomes aligned with the exteriorline 19 on wall 12, the patient is alerted to the fact that thepredetermined percentage of the dose of drug has been delivered. At thispoint, the patient simply swallows the device and the remaining portionof drug in device 10 is administered through the GI tract.

In another embodiment, a plurality of lines 19 are provided on wall 12.Each of the lines 19 is positioned to align with interface 18 after thedevice 10 has been retained in the mouth for a predetermined period oftime, e.g., a one hour marking line, a two hour marking line, etc. Inthis way, the patient can easily monitor the duration of drug delivery,even without access to a clock.

In another preferred embodiment of the present invention, the mechanismfor signaling the patient comprises a contrast in taste between the drugformulation 14 and the hydrophilic polymer driving layer 16. In thisembodiment, the flavor of the drug formulation 14 is chosen to provide asharp contrast with the flavor of the hydrophilic polymer driving layer16. Preferably, the drug formulation contains a flavoring agent which isenjoyed by the patient, while the hydrophilic polymer layer contains aflavoring agent having an unpleasant taste. For example, the drug can beflavored with peppermint oil while the hydrophilic polymer layer isflavored with a salt (e.g., NaCl). The flavor of the drug formulation 14can be achieved by any number of flavoring techniques known in the art.For example, the drug itself may have a natural flavor which itselfadequately contrasts with the natural flavor of the hydrophilic polymerdriving layer 16. On the other hand, a number of pharmaceuticallyacceptable flavoring agents may be mixed with either the drugformulation 14 and/or the hydrophilic polymer in layer 16 in order toprovide the appropriate taste contrast. Suitable pharmaceuticallyacceptable flavoring agents, both natural and synthetic, are known inthe art. See Remington's Pharmaceutical Sciences, 14th Ed., pp1321-1338.

In another preferred embodiment of the present invention, a flavoringagent is incorporated in the wall 12. Preferably, the wall 12 contains aflavoring agent which leaches out into the saliva as soon as the device10 is placed in the patient's mouth. Most preferably, the wall 12contains a flavoring agent which is enjoyed by the patient and inparticular can be the same flavoring agent used to flavor the drugformulation 14. In general, the wall 12 will contain up to about 20 wt %flavoring agent. Any of the pharmaceutically acceptable flavoring agentsmentioned above may be incorporated into wall 12.

Osmotic delivery device 10 can be manufactured with a wall 12 formed ofa material that does not adversely affect the agent 14 (e.g., a drug),the osmagent, if any is present, and the hydrophilic polymer in layer16. The material forming wall 12 should also not adversely affect thebuccal tissues of the patient. In addition, the material forming wall 12is permeable to the passage of an external aqueous fluid 15, such aswater and biological fluids naturally present in the oral cavity (e.g.,saliva), while remaining essentially impermeable to the passage ofhydrophilic polymer, and optionally impermeable to the passage ofagents, including drugs, osmagents, and the like. The selectivelysemipermeable materials forming wall 12 are insoluble in fluidsnaturally present in the oral cavity. Typical materials for forming wall12 include semipermeable polymers known to the art as osmosis andreverse osmosis membranes, such as cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, agar acetate, amylose triacetate, beta glucanacetate, acetaldehyde dimethyl acetate, cellulose acetate ethylcarbamate, polyamides, polyurethanes, sulfonated polystyrenes, celluloseacetate phthalate, cellulose acetate methyl carbamate, cellulose acetatesuccinate, cellulose acetate dimethylaminacetate, cellulose acetateethyl carbamate, cellulose acetate chloracetate, cellulose dipalmatate,cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate,cellulose acetate valerate, cellulose acetate succinate, cellulosepropionate succinate, methyl cellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, cross-linked selectivelysemipermeable polymers formed by the coprecipitation of a polyanion anda polycation as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;3,541,005; 3,541,006; and 3,546,142, semipermeable polymers as disclosedby Loeb and Sourirajan in U.S. Pat. No. 3,133,132, lightly cross-linkedpolystyrene derivatives, cross-linked poly(sodium styrene sulfonate),poly(vinylbenzyltrimethyl ammonium chloride), cellulose acetate having adegree of substitution up to 1 and an acetyl content up to 21%,cellulose diacetate having a degree of substitution of 1 to 2 and anacetyl content of 21 to 35%, cellulose triacetate having a degree ofsubstitution of 2 to 3 and an acetyl content of 35 to 44.8%, asdisclosed in U.S. Pat. No. 4,160,020. Generally, semipermeable materialsuseful for forming wall 12 will have a fluid permeability of 10⁻⁵ to10⁻¹ (cc·mil/cm² ·hr·atm) expressed per atmosphere of hydrostatic orosmotic pressure difference across semipermeable wall 12 can be used forthe intended purpose.

In accordance with one preferred embodiment of the present invention, atleast a portion of the material forming wall 12 is sufficientlytranslucent to allow a patient to see the relative amounts ofhydrophilic polymer 16 and drug 14 remaining in compartment 13. Examplesof suitable translucent materials include the cellulosic polymersmentioned above. Generally, the wall 12 will contain a sufficient amountof translucent material to enable the patient to see the drug layer 14and the hydrophilic polymer layer 16 within compartment 13. Suitableamounts of translucent materials will depend upon the translucency ofthe wall material, the methods and conditions under which the wallmaterials are formed, as well as the amount of contrast in the colors ofthe drug and hydrogel layers. Suitable amounts of translucent materialscan be easily determined through routine experimentation using theexamples herein.

The expression "active agent", as used herein includes any beneficialagent or compound, that can be delivered from the device into the oralcavity to produce a beneficial and useful result. The agent can beinsoluble to very soluble in the exterior fluid. For example, the agentcan be very soluble in fluid 15 that enters compartment 13 and functionas its own osmotically effective solute, or it can be poorly soluble inthe fluid and be mixed with an osmotically effective compound that issoluble in the fluid for delivering an agent from the device.

In the specification and the accompanying claims, the term "agent"includes drug, and the term "drug" includes any physiologically orpharmacologically active substance that produces a local or systemiceffect when administered to the oral cavity of a human. The term"physiologically" as used herein denotes the administration of a drug toproduce normal levels and functions. The term "pharmacologically"denotes variations in response to amount of drug administered to thehost. Stedman's Medical Dictionary, 1966, published by Williams andWilkins, Baltimore, Md. The active drug that can be delivered includesinorganic and organic drugs without limitations, those drugs that act onthe central nervous system, depressants, hypnotics, sedatives, psychicenergizers, tranquilizers, anticonvulsants, muscle relaxants,antiparkinson agents, analgesics, anti-inflammatory, local anesthetics,muscle contractants, anti-microbials, anti-fungals, anti-malarials,hormonal agents, contraceptives, sympathomimetics, diuretics,anti-parasitics, neoplastics, hypoglycemics, ophthalmics, electrolytes,diagnostic agents, and cardiovascular drugs.

Exemplary drugs that are very soluble in water and can be delivered bythe devices of this invention include nystatin, chlorhexidine,clonidine, sodium fluoride, prochlorperazine adisylate, ferrous sulfate,aminocaproic acid, potassium chloride, mecamylamine hydrochloride,procainamide hydrochloride, amphetamine sulfate, benzphetaminehydrochloride, isoproterenol sulfate, methamphetamine hydrochloride,phenmetrazine hydrochloride, bethanechol chloride, methacholinechloride, pilocarpine hydrochloride, atropine sulfate, methascopolaminebromide, isopropamide iodide, tridihexethyl chloride, phenforminhydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride,metoprolol tartrate, cimetidine hydrochloride, and the like.

Exemplary drugs that are poorly soluble in water and that can bedelivered by the devices of this invention include nicotine base, retinA, ibuprofen, diphenidol, meclizine hydrochloride, prochlorperaziminemaleate, phenoxybenzamine, thiethylperazine maleate, anisindone,diphenadione erythrityl tetranitrate, dizoxin. isofuraphate, reserpine,acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide,tolzamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminumaspirin, methotrexate, acetyl sulfisoxazole, erythromycin, progestins,esterogenic progestational hormones, corticosteroids, hydrocortisone,hydrocorticosterone acetate, cortisone acetate, triamcinolone,testosterone, testosterone esters, methyltesterone, 17β-estradiol,ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,17β-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindone, norethiderone, progesterone, norgesterone, norethynodrel,and the like.

Examples of other drugs that can be delivered by the osmotic deviceinclude aspirin, indomethacin, naproxen, fenoprofen, sulidac,diclofenac, ibuprofen, indoprofen, nitroglycerin, propranolol,metoprolol, valproate, oxprenolol, timolol, atenolol, alprenolol,cimetidine, clonidine, imipramine, levodopa, chlorpromazine, reserpine,methyl-dopa, dihydroxyphenylalanine, pivaloyloxyethyl ester ofα-methyldopa hydrochloride, theophylline, calcium gluconate, ferrouslactate, vincamine, diazepam, phenoxybenzamine, α-blocking agents,polypeptides, proteins, insulin and the like. The beneficial drugs areknown to the art in Pharmaceutical Sciences, by Remington 14th Ed.,1979, published by Mack Publishing Co., Easton, Penn.; The Drug, TheNurse, The Patient, Including Current Drug Handbook, 1974-1976, byFalconer, et al., published by Saunder Company, Philadelphia, Penn.; andMedicinal Chemistry, 3rd Ed., Vol. 1 and 2, by Burger, published byWiley-Interscience, New York.

The drug can be in various forms, such as uncharged molecules, molecularcomplexes, pharmacologically acceptable salts such as hydrochlorides,hydrobromides, sulfate, laurylate, palmitate, phosphate, nitrite,borate, acetate, maleate, tartrate, oleate, and salicylate. For aciddrugs, salts of metals, amines or organic cations, for examplequaternary ammonium can be used. Derivatives of drugs such as esters,ethers and amides can be used. Also, a drug that is water insoluble canbe used in a form that is a water soluble derivative thereof to serve asa solute, and on its release from the device is converted by enzymes,hydrolyzed by body pH or other metabolic processes to the originalbiologically active form. Drugs in the form of polypeptides andproteins, which are susceptible to being broken down in the GI tract,can also be delivered systemically by the device of the presentinvention by absorption through the buccal membranes of the oral cavity.

In order to withstand the conditions of use within the oral cavity (i.e.patient sucking and chewing of the delivery device), the drug layer 14should contain a gelling or suspending agent which prevents the exteriorwall from collapsing during use. Representative gelling or suspendingagents include acacia, agar-agar, calcium carrageenan, alginic acid,algin, agarose powder, collagen, colloidal magnesium silicate, colloidalsilicon dioxide, sodium carboxy methyl cellulose, partially cross-linkedpolyacrylic acid, polyvinyl pyrrolidone, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethyleneoxide, pectin, gelatin, calcium silicate and mixtures thereof.

Generally, the drug layer 14 typically contains from about 0.5 to about99.9 wt % of a gelling or suspending agent, depending on the loading ofdrug/beneficial agent in layer 14 and its solubility in the fluidentering the device. Most preferably, the gelling or suspending agent ispolyethylene oxide, hydroxy propyl methyl cellulose or mixtures thereof.

The agent including drug, can also be present in the compartment with abinder, dispersant, wetting agent and lubricant. Representative of theseinclude binders like polyvinyl pyrrolidone, and hydroxypropyl methylcellulose, wetting agents such as fatty amines and fatty quaternaryammonium salts, and lubricants such as magnesium stearate and stearicacid. The phrase drug formulation indicates the drug is present in thecompartment accompanied by a gelling or suspending agent, an osmagent, abinder, dye or the like.

The amount of agent initially present in the device is not critical,however it is preferred to initially provide an amount of active agent,which agent is soluble in fluid entering the device, in excess of theamount that can be dissolved in the fluid that enters the device. Underthis physical state, when the agent is in excess, the device willosmotically operate to give a substantially constant rate of release.Generally, the device can house from about 0.05 ng to 500 mg or more ofdrug, carrier, fillers, excipients, etc. with individual devicescontaining for example, 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, andthe like.

The osmagent present in the device, when used according to the mode ofthe invention where the beneficial agent is not itself osmoticallyactive, are osmotically effective compounds soluble in the fluid thatenters the device, and exhibits an osmotic pressure gradient across thesemipermeable wall against the exterior fluid. Osmotically effectiveosmagents useful for the present purpose include magnesium sulfate,magnesium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassiumchloride, sodium sulfate, d-mannitol, urea, sorbitol, inositol,raffinose, sucrose, glycose, hydrophilic polymers such as cellulosepolymers, mixtures thereof, and the like. The osmagent is usuallypresent in an excess amount, and it can be in any physical form, such asparticle, powder, granule, and the like. The osmotic pressure inatmospheres of the osmagents suitable for the invention will be greaterthan zero and generally up to about 500 atm, or higher.

The hydrophilic polymer layer 16 suitable for the purpose of theinvention are swellable, hydrophilic polymers which interact with waterand aqueous biological fluids and swell or expand to an equilibriumstate. The polymers exhibit the ability to swell in water and retain asignificant portion of the imbibed water within the polymer structure.The polymers swell or expand to a very high degree, usually exhibiting a2 to 50 fold volume increase. The polymers can be noncross-linked orcross-linked. The swellable, hydrophilic polymers are in one presentlypreferred embodiment lightly cross-linked, such cross-links being formedby covalent ionic bonds or hydrogen bonds. The polymers can be of plant,animal or synthetic origin. Hydrophilic polymers suitable for thepresent purpose include poly(hydroxy alkyl methacrylate) having amolucular weight of from 30,000 to 5,000,000; poly(vinylpyrrolidone)having moleuclar weight of from 10,000 to 360,000; anionic and cationichydrogels; polyelectrolyte complexes; poly(vinyl alcohol) having a lowacetate residual, cross-linked with glyoxal, formaldehyde, orglutaraldehyde and having a degree of polymerization from 200 to 30,000;a mixture of methyl cellulose; cross-linked agar and carboxymethylcellulose; a water insoluble, water swellable copolymer produced byforming a dispersion of finely divided copolymer of maleic anhydridewith styrene, ethylene, propylene, butylene or isobutylene cross-linkedwith from 0.001 to about 0.5 moles of saturated cross-linking agent permole of maleic anhydride in copolymer; water swellable polymers ofN-vinyl lactams, and the like.

Other polymers include polymers that form hydrogels such as Carbopol®acidic carboxy polymers having a molecular weight of 450,000 to4,000,000; Cyanamer® polyacrylamides; cross-linked water sweallableindene-maleic anhydride polymers, Goodrite® polyacrylic acid having amolecular weight of 80,000 to 200,000; Polyox® polyethylene oxidepolymers having molecular weight of 100,000 to 5,000,000 and higher;starch graft copolymers; Aqua-Keeps® acrylate polymer polysaccharidescomposed of condensed glucose units such as diester cross-linkedpolyglucan, and the like. Representative polymers that form hydrogelsare known to the prior art in U.S. Pat. No. 3,865,108 issued to Hartop;U.S. Pat. No. 4,002,173 issued to Manning; U.S. Pat. No. 4,207,893issued to Michaels; and in Handbook of Common Polymers, by Scott andRoff, published by the Chemical Rubber Company, Cleveland, Ohio.

For the purpose of the invention, the phrase agents with degrees ofsolubility as used herein indicates, agents that are insoluble to verysoluble in aqueous biological fluids present in the oral cavity, such assaliva. Further for this purpose, an insoluble agent indicates asolubility of less than 25 mg of agent per ml of fluid, a poorly solubleagent is one that dissolves in the range of about 25 mg to 150 mg ofagent per ml of fluid, a soluble agent dissolves about 150 mg to 600 mgof agent per ml of fluid. While the presently preferred embodiments havebeen described with reference to poorly or very soluble agents, it is tobe understood the device can be used to deliver other agents.

Typical methods used for the measurement of solubility are chemical andelectrical conductivity. Details of various methods for determiningsolubilities are described in United States Public Health ServiceBulletin, No. 67 of the Hygienic Laboratory; Encyclopedia of Science andTechnology, Vol. 12, pages 542 to 556, 1971, published by McGraw-Hill,Inc,; and Encyclopedia Dictionary of Physics, Vol. 6, pages 547 to 557,1962, published in Pergamon Press, Inc.

The interaction of the hydrophilic polymer-drug interface can beascertained by placing a film formed of a hydrophilic polymer in contactwith an aqueous solution containing an active agent, and sometimes anosmagent, and observing the modification of the polymer at thepolymer-aqueous environment. The surface of the polymer should bemodified in situ during operation of the device. If a precipitate formsalong the outer surface of the polymer, the polymer and the solution aresuitable for operating the compartment of the device. A representativeprocedure that can be used consists in measuring the percent weight gainfor various polymers immersed in a saturated solution of a drug or anosmagent. The procedure broadly indicates interface absorption activity.That is, if there is little absorption by the polymer, there iscorrespondingly a little gain in weight and the polymer is suitable forthe purpose. Similarly, if there is a large gain in weight indicating alarge volume absorbed, the polymer is not preferred for the purpose.FIG. 4 of U.S. Pat. No. 4,327,725 represents the percent weight gain for4 polymers (A is Klucel H® polymer; B is Polyox COAG® polymer; C isCarbopol-934® polymer; and D is Na Carbopol-934® polymer) immersed in asaturated solution of NaCl as a function of the imbibition pressure ofthe polymer. Polymer imbibition pressure of any given hydrophilicpolymer can be determined according to the procedure outlined in Corteseet al U.S. Pat. No. 4,327,735 column 10, line 67 to column 12, line 24,which is incorporated herein by reference.

The device of the invention is manufactured by standard techniques. Forexample, in one embodiment, the agent and other ingredients that may behoused in one area of the compartment adjacent to the passageway, arepressed into a solid possessing dimension that corresponds to theinternal dimensions of the area of the compartment the agent willoccupy, or the agent and other ingredients and a solvent are mixed intoa solid or semisolid form by conventional methods such as ballmilling,calendering, stirring or rollmilling, and then pressed into apreselected shape. Next, a layer of a hydrophilic polymer is placed incontact with the layer of agent in a like manner, and the two layerssurrounded with a semipermeable wall. The layering of agent formulationand hydrophilic polymer can be fabricated by conventional two-layerpress techniques. The wall can be applied by molding, spraying ordipping the pressed shapes into a wall forming material. Another andpresently preferred technique that can be use for applying the wall isthe air suspension procedure. This procedure consists of suspending andtumbling the pressed agent and dry hydrophilic polymer in a current ofair and a wall forming composition until the wall is applied to theagent-hydrophilic polymer composite. The air suspension procedure isdescribed in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., vol. 48,pages 451 to 459, 1979; and ibid, Vol. 49, pages 82 to 84, 1960. Otherstandard manufacturing procedures are described in Modern PlasticsEncyclopedia, Vol. 46, pages 62 to 70, 1969; and in PharmaceuticalSciences, by Remington, Fourteenth Edition, pages 1626 to 1678, 1970,published by Mack Publishing Company, Easton, Penn.

Exemplary solvents suitable for manufacturing the wall include inorganicand organic solvents that do not adversely harm the wall formingmaterial, and the final device. The solvents broadly include membersselected from the group consisting of aqueous solvents, alcohols,ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents,cycloaliphatic, aromatics, heterocyclic solvents, and mixtures thereof.Typical solvents include acetone, diacetone alcohol, methanol, ethanol,isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate,isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methylpropyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether,ethelene glycol monoethyl acetate, methylene dichloride, ethylenedichloride, propylene dichloride, carbon tetrachloride, nitroethane,nitropropane, tetrachloroethane, ethyl ether, isopropyl ether,cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane,tetrahydrofuran, diglycol methyl ether, water and mixtures thereof suchas acetone and water, acetone and methanol, acetone and ethyl alcohol,methylene dichloride and methanol, and ethylene dichloride and methanol,and mixtures thereof.

The expression "passageway" as used herein comprises means and methodssuitable for releasing the agent from the system. The expressionincludes one or more aperture, orifice or bore through wall 12 formed bymechanical procedures, or by eroding an erodible element, such as agelatin plug, in the oral cavity. In cases where the semipermeablemembrane is sufficiently permeable to the passage of beneficialagent/drug, the pores in the membrane may be sufficient to release theagent/drug in therapeutically effective amounts. In such cases, theexpression "passageway" refers to the pores within the membrane walleven though no bore or other orifice has been drilled therethrough. Adetailed description of osmotic passageways and the maximum and minimumdimensions for a passageway are disclosed in U.S. Pat. Nos. 3,845,770and 3,916,899, the disclosures of which are incorporated herein byreference. Preferaby, 1 to 2 passageways 17 are provided in device 10 asshown in the Figures.

The expressions "extended period of time" and "extended delivery period"as used herein generally refers to periods greater than about 0.5 hours,preferably about 0.5 to 12 hours, more preferably about 0.5 to 6 hours,most preferably about 1-4 hours.

The following examples are merely illustrative of the present inventionand should not be considered as limiting the scope of the invention inany way.

EXAMPLE 1

An osmotic therapeutic device for the controlled and continuous releaseinto the oral cavity of the beneficial antifungal drug nystatin was madeas follows: 43 mg of nystatin, 193 mg of polyethylene oxide (PolyoxN-10), 13 mg of hydroxy propyl methyl cellulose (HPMC E-5), 3 mg ofsodium saccharin, 13 mg of oil of anise and 1 mg of magnesium stearateare mixed thoroughly and pressed in a Manesty Layer Press with a 5/8inch oval punch using a pressure head of 2 tons to produce a layer ofthe drug composition. The nystatin had a natural yellow color while theremaining ingredients had a natural white color. Accordingly, the drugcomposition had a natural pale yellow color. The oil of anise was addedas a flavoring agent to mask the objectionable bitter taste of thenystatin.

Next, the driving layer of the device was formulated by mixing 114 mg ofpolyethylene oxide (Polyox Coag), 52 mg NaCl, 9 mg hydroxy propyl methylcellulose (HPMCE-5), 2 mg Fe₂ O₃ as a colorant and 1 mg of magnesiumstearate. The formulation was added to the Manesty Layer Press andpressed to form a layer of hydrophilic polymer in contact with the druglayer. The hydrophilic polymer driving layer had a reddish-brown colordue to the ferric oxide.

Next, a semipermeable wall was formed by blending 24 g of celluloseacetate having an acetyl content of 39.8% with 1103 ml of acetone, 97 mlof water and 16 g of hydroxy propyl cellulose (KLUCEL EF), and spraycoating the two layered compartment forming member in an air suspensionmachine having a 0.4 kg charge until a 6 mil thick semipermeable wallsurrounds the compartment. The coated device was dried for 72 hours at35° C., and then two 25 mil passageways were laser drilled through thesemipermeable wall to connect the layer of drug with the exterior of thedevice. The KLUCEL component of the wall material made the wallsufficiently translucent to clearly see the yellow drug layer and thereddish-brown hydrophilic polymer layer. Accompanying FIG. 5 depicts thecumulative amount of nystatin released by the device when retained inthe mouth of a human over a period of 3 hours and compares the nystatinrelease profile with the profiles of the nystatin delivery devicesdescribed in Comparative EXAMPLES 1 and 2.

Comparative EXAMPLE 1

A chewing gum containing nystatin is prepared in accordance with Example1 of U.S. Pat. No. 4,238,475 with the following exceptions. Each stickof gum is loaded with 43 mg of nystatin (the same dose of nystatinutilized in Example 1) instead of 5 mg nystatin. Thus, the weightpercent of nystatin in each stick of chewing gum is about 1.5 wt %rather than 0.18 wt %. All other ingredients are prepared as in Example1 of U.S. Pat. No. 4,238,475. Accompanying FIG. 5 depicts the cumulativeamount of nystatin released into the mouth of a human chewing the gumover a period of 3 hours.

Comparative EXAMPLE 2

A nystatin containing chewing gum is prepared as in comparative Example1 except that the conventional chewing gum base is replaced withethylene vinyl acetate having a vinyl acetate content of 51%. The doseof nystatin in each stick of gum is again 43 mg or about 1.5 wt %. Thegum is chewed by a human for a period of 3 hours and the cumulativeamount of nystatin released is shown in FIG. 5.

A comparison of the three nystatin delivery profiles plotted in FIG. 5shows that the device of the present invention releases nystatin intothe oral cavity at a substantially constant delivery rate. This is shownby the substantially straight line release profile for Example 1. Bycomparison, the chewing gums of Comparative Examples 1 and 2 have atendency to release a major portion of the nystatin within the first 20minutes of chewing. For Comparative Example 1, the chewing gum releasesabout 75% of the total nystatin dose in the first 20 minutes. For theEVA base gum of Comparative Example 2, approximately 40% of the nystatindose is delivered within the first 20 minutes. The curves shown in FIG.5 illustrate that the chewing gums of Comparative Examples 1 and 2 areill-suited for delivering nystatin to the oral cavity over periods ofgreater than about 1 hour.

EXAMPLE 2

An osmotic therapeutic device manufactured in the form of an oraldelivery device for delivering chlorhexidine diacetate into the oralcavity was manufactured as follows: first a 150 mg compositioncomprising 3.7% chlorhexidine diacetate, 90.8% polyethylene oxide(Polyox N-10), 5% hydroxy propyl methyl cellulose (HPMC E-5) and 0.5%magnesium stearate was prepared by blending the four ingredients into ahomogenous blend, and then pressed into a solid mass in a commerciallyavailable Manesty tableting machine set to a Stoke's hardness of 7 kg.The resulting drug-containing layer had a white color.

Next, a 100 mg composition comprising 68.5% polyethylene oxide having amolecular weight of about 5,000,000 (Polyox Coag), 20% NaCl, 5% HPMCE-5, 5% Carbomer 934 P, 1% ferric oxide colorant and 0.5% magnesiumstearate was added to the tableting machine and pressed into a solidmass in contact with the drug-containing layer. The hydrophilic polymerlayer had a reddish-brown color, due to the ferric oxide, providing agood color contrast with the white drug-containing layer. Then, the twolayered mass was coated in a standard air suspension machine with asemipermeable polymeric wall formed from a 4% solids solution consistingof 60 wt % cellulose acetate having an acetyl content of 39.8%, in asolvent consisting of 90% acetone and 10% water, and 40 wt % hydroxypropyl cellulose (KLUCEL EF). The resulting semipermeable wall had athickness of 5 mils. The KLUCEL component of the wall material made thewall translucent, making it possible to see both the whitedrug-containing layer and the reddish-brown hydrogel layer within theinner compartment of the device. Finally, one osmotic passageway, havinga diameter of 25 mils, was drilled through the wall facing thechlorhexidine-containing layer for delivering it from the device.

EXAMPLE 3

An oral osmotic therapeutic device for delivering ibuprofen ismanufactured by following the procedure of Example 2, with allconditions and procedures as described, except in this example the layerof drug formulation comprises 20.5% ibuprofen, 66.5% Polyox N-10, 5%HPMC E-5, 7.5% sodium carbonate and 0.5% magnesium stearate. Theibuprofen containing layer has a white color. The hydrophilic polymerlayer comprises 64.3% Polyox Coag, 29.2% NaCl, 5% HPMC E-5, 1% ferricoxide colorant, and 0.5% magnesium stearate. The resulting hydrogellayer has a reddish-brown color. The translucent semipermeable wall is 5mils thick and comprises 60% cellulose acetate having an acetyl contentof 39.8% and 40% Klucel EF, formed from a solvent consisting essentiallyof 90% acetone and 10% water. One passageway with a diameter of 25 milsis drilled in the side of the device adjacent the ibuprofen-containinglayer.

Unlike in Example 2, following drilling of the passageway, the device isovercoated with a mixture comprising 20 wt % ibuprofen and 80 wt % HPMC.The overcoating layer has a thickness of 3 mils. The ibuprofencontaining overcoat provides a loading dose which is quickly deliveredto the patient upon retention in the mouth. Generally, the overcoatlayer will be completely removed by patient sucking within about 15 to30 minutes. This is especially useful in cases where there is an initialdelay between the time when the device is placed in the mouth of thepatient and the time when the device begins pumping drug.

EXAMPLE 4

An osmotic therapeutic device for the controlled and continuous releaseof nystatin into the oral cavity is made as follows. The drugformulation layer comprises 30 wt % nystatin, 50 wt % Polyox N-10, 18 wt% spearmint oil, 1 wt % sodium saccharin and 1 wt % magnesium stearate.The ingredients are mixed thoroughly and pressed in a Manesty LayerPress with a 5/8 inch oval punch using a pressure head of 2 tons toproduce a layer of the drug composition.

The driving layer of the device is formulated by mixing 75 wt %polyethylene oxide having a molecular weight of about 5,000,000 (PolyoxCoag), 20 wt % NaCl, 4 wt % hydroxypropylmethyl cellulose (HPMC E-5) and1 wt % magnesium stearate. The ingredients are mixed and added to theManesty Layer Press and pressed to form a layer of hydrophylic polymerin contact with the drug layer.

A semipermeable wall is formed by blending 70 wt % cellulose acetatehaving an acetyl content of 39.8% with a mixture of acetone and water,10 wt % polyethylene glycol (PEG 3350), 1 wt % sodium saccharin and 19wt % spearmint oil. The two-layer tablet is spray coated with thecellulose acetate blend in an air suspension machine until a 6 mil thicksemipermeable wall surrounds the tablet. The coated tablet is dried for72 hours at 35° C. and then two 25 mil passageways are laser drilledthrough the semipermeable wall on the drug layer side of the tablet.When placed in a patient's mouth, the device immediately releases apleasant spearmint taste.

While certain preferred embodiments of the invention have been describedin detail herein, those skilled in the art will appreciate that numerousmodifications of the described embodiments can be made without departingfrom the spirit and scope of the invention as defined in the appendedclaims.

We claim:
 1. An osmotic device for treatment of Parkinson's disease bythe controlled delivery of a drug comprising levodopa to the mucosa ofthe oral cavity of a patient over an extended delivery period of between0.5 to 12 hours, the device comprising:a wall defining a compartment andan exit passageway, the wall being formed of a semipermeable material; adrug layer comprising a dose of 0.05 ng to 500 mg levodopa and asuspending agent therefore located in the compartment adjacent the exitpassageway, the exit passageway communicating the drug layer with theexterior, and a driving layer comprising a hydrophilic polymer locatedin the compartment adjacent the drug layer and opposite the exitpassageway; wherein the device has a smooth oval shape with an aspectratio in the range of about 1.2:1 to about 3:1, a height of about 0.5 toabout 10 mm, and a volume of less than about 2 cm³ and delivers levodopathrough the exit passageway to the mucosa within the oral cavity.
 2. Theosmotic device of claim 1, wherein the device further comprises up to 20wt % of a flavoring agent in the drug-containing layer said flavoringagent having a taste which contrasts with the hydrophilic polymer layertaste for signaling the patient when the dose of the drug has beendelivered from the device.
 3. The osmotic device of claim 1, wherein thedevice further comprises a coloring agent in the hydrophilic polymerlayer, said coloring agent having a color which contrasts with the colorof the drug-containing layer for signaling the patient when the dose ofthe drug has been delivered from the device, and wherein thesemipermeable wall comprises a material which permits visual inspectionof the drug present in the compartment.
 4. The osmotic device of claim3, that also displays the amount of drug present in the device.
 5. Theosmotic device of claim 1, wherein the semipermeable wall has anovercoating containing drug.
 6. The osmotic device of claim 1, whereinthe drug containing layer also contains an osmagent.
 7. The osmoticdevice of claim 6, wherein the osmagent comprises mannitol.
 8. Theosmotic device of claim 1, wherein the suspending agent comprises acellulosic polymer.
 9. The osmotic device of claim 8, wherein thecellulosic polymer is selected from the group consisting of sodiumcarboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, and hydroxyproplymethyl cellulose.
 10. The osmotic device ofclaim 8, wherein the suspending agent comprises hydroxypropyl cellulose.11. The osmotic device of claim 1, wherein the hydrophilic polymercomprises a polysaccharide.